1. Field of the Invention
The present invention relates to novel and therapeutically useful derivatives of phenytoin. More particularly, the present invention concerns the discovery of a group of novel derivatives of phenytoin which offer enhanced solubility over phenytoin per se.
These compounds are extremely useful as anticonvulsants, antiepileptics and antiarrhythmics and can be administered to warm-blooded animals (e.g., humans) per se or in pharmaceutical composition form when admixed with a suitable nontoxic pharmaceutically acceptable carrier.
2. Description of the Prior Art
A pharmaceutical and medical need exists for new and useful compounds indicated from the management of epilepsy and other types of convulsive states, and cardiac arrythmics. The need exists because compounds such as 5,5-diphenylhydantoin, generally referred to as diphenylhydantoin or phenytoin, which is most commonly and widely used for the treatment of these conditions possess extremely low solubility and hence, low bioavailability per se as well as from pharmaceutical dosage forms. For example, 5,5-diphenylhydantoin which has a therapeutic index between 1 and 2, a pKa of 8.3, and a solubility of less than 2 mg. in 100 ml at 37.degree. C. often produces unpredictable and erractic release patterns, both in vitro and in vivo. Also, when 5,5-diphenylhydantoin is orally administered in the form of its sodium salt, it frequently causes gastric irritation due to the alkalinity of the administered dosage form. For intravenous administration, sodium 5,5-diphenylhydantoin is generally used in a formulation comprising 40% propylene glycol and 10% alcohol in water, adjusted with sodium hydroxide to a high alkaline pH. Intravenous administration of this formulation frequently leads to precipitation of 5,5-diphenylhydantoin as well as erractic blood levels. Intramuscular use of sodium 5,5-diphenylhydantoin has been shown to precipitate 5,5-diphenylhydantoin at the injection site leading to delayed and erractic 5,5-diphenylhydantoin release. Other hydantoins have similar problems to those seen with 5,5-diphenylhydantoin. This common and wide use of the hydantoins with their accompanying disadvantages, and specifically, their low solubilities, creates an immediate and pressing need for new and useful pharmaceutical compounds that possess therapeutic properties useful for treating epilepsy and other convulsive states, and cardiac arrythmics, while remaining essentially free from the unwanted effects associated with the prior art compounds.
U.S. Pat. No. 3,595,862 claims the potential usefulness of N,N'-bis(acyloxymethyl)5,5-diphenylhydantoin compounds as effective anticonvulsants. The compounds of this patent include those in which the acyloxy groups are acetoxy, acryloxy, methacryloxyloxy, propionoxy and benzoyloxy. The compounds are inferior in solubility to the compounds claimed in this application and in fact have solubility characteristics similar to 5,5-diphenylhydantoin itself.